Results from DuchenneConnect Study - PPMD Webinar Follow up

Thank you for participating in last week’s webinar on DuchenneConnect data! Many of you asked questions during the webinar that we were unfortunately unable to get to within the hour. We have done our best to answer all questions submitted.

Please see the list of Q&A's following the webinar video below, and let me know if you have any additional follow up questions!

Question: You may have already covered this but are these stats being reviewed against the type of mutation? There are a lot of parents who want to understand how the mutations play a role in progression.

So far there is no observed effect based on the exact mutation, but since there are hundreds of mutation types the number of people with a given mutation and on a given treatment regimen becomes really small. Most of the mutations look to have the same effect. We will be better able to tease out the effect of individual DMD gene mutations and disease severity with more people registering. Also, Dr. Nelson believes that much of the variation in how severe the disease is may be from mutations/variants in the DNA elsewhere in one of the other 20,000 proteins. This is the reason to search for ‘modifier genes’ which his laboratory is pursuing by sequencing the whole genomes of some individuals with Duchenne.

Question: Can you speak on growth hormone treatment and steroids? Stature is a result but shorter stature seems to be of a benefit for DMD population so what is the goal of growth hormone? Is there any proof of muscle benefits from Growth Hormone?

To date, we have no evidence that growth hormone (hGH) contributes to muscle growth or strength. Its use is purely to increase height. While some boys are not bothered by their height, some are very effected by having short stature. Using hGH may allow them to grow several inches. There is not enough data in DuchenneConnect to observe any positive benefit on strength from hGH use. If hGH is used more commonly in boys prior to loss of ambulation, we may be able to observe an effect.

Question: Did I hear you say that an alternate dose of Deflazacort may be better than a daily regimen? Or did I misunderstand that?

One of the surprising results (at least to Dr. Nelson) was that there was a trend to higher age at WC use for the small number (11) of boys who reported using a ‘non-daily’ regimen of Deflazacort. This was not statistically significant and may be due to a chance artifact due to small numbers.

Question: Is Deflazacort prescribed in the US? From what I've read on the internet, it's only available in Canada.

Deflazacort is prescribed in the US, but is not available in this country. Most families that use deflazacort order their medication from Canada or UK using a prescription from their US physician. The medication is then mailed to them.

Question: Were you able to examine any data related to the age that steroids are started?

We unfortunately do not have this data in the registry yet. We are currently revising the Profile Survey and plan to add this question. Looking at cumulative dose that boys with DMD have taken, and age at initiation would be great to explore. There is huge variation in physician initiation for steroids, because this issue has not been well addressed. It is only in the last several years that physicians are likely to have started steroids early after diagnosis, so those data may not become apparent for a couple of years, but will be really interesting to observe.

Question: Do you have data on age steroids are started at and age of wc use?

We do not have data on the age that steroids are started, but we do ask for the age at fulltime wheelchair use.

Question:In regards to the question whether DMD patients have participated in clinical trials, can a follow-up question be added to ask if no, then why?

Yes, we are currently revising the Profile Survey and we plan to ask additional questions about clinical trial participation, including why some people choose not to participate.

Question:Is the age of WC use the same as loss of independent walking?

Yes.

Question: Is the age of WC specific to the age of loss of ability to walk independently and not referring to the use of WC for long distances while still ambulant?

Yes, the former. We ask for the age when fulltime wheelchair use is required. Other questions weed out those who use WC for long distances only.

Question: What is the %age of 10-12 yr old DMD subjects are still ambulatory?

In DuchenneConnect, we have 196 boys with DMD between 10-12 years old, and 81% are still ambulatory, with a strong effect observed for current steroid users versus non-users (see slide number 16).

Question: If a person is taking multiple supplements VitaminD+Calcium+CoQ10, how have you considered them in your analysis?

Most of the individuals who are taking Vitamin D are also taking Calcium. Thus, the relative effect from each of those is difficult to observe separately. However, for each of the supplements we can measure their independent effect and when taken all together observe if there is further improvement in age at WC use. But the numbers get small, as we must correct for 'steroid' use and also for 'ACE inhibitor' use and also for other supplement use. So we are at the mercy of what data are reported. There are 13 patients taking the regimen Steroid, ACEI, Vit D, Calcium and NOT taking CoQ10 VS 11 who report taking Steroid, ACEI, Vit D, Calcium and CoQ10. Even those these two numbers are small, there is a statistically significant increase in age at WC use for those boys who report the addition of CoQ10 to that regimen. Keep in mind that a benefit of the DuchenneConnect data is that it is likely to be recording practices over many years by parents. Thus the time period over which any of these supplements/vitamins/drugs are working is not clear (yet), but with more data and more information about what DMD patients have done, we may get better clarity.

Question:Can you tell us how you define Becker?

The parents/registrant select Becker as their diagnosis from the following options: DMD, BMD, DMD/BMD/unclear, manifesting carrier, confirmed carrier, at risk to be a carrier. So this is ‘self-reported’, the clinical boundary between individuals with a molecular defect in DMD gene that results in no dystrophin expression and yet remain ambulatory past 16 is increasing. So the ‘clinical’ definition of Becker is rather less important. I would imagine that many who indicate DMD/BMD/unclear have DNA diagnosis that is not completely predictive of clinical course.

We do not have a current study that is focused on the adverse effects of steroids, but hopefully the data that we are collecting can be used for this purpose in the future. It would also be good to have parents report ‘steroid intolerance’ for weight gain/behavioral issues.

Question:My son 8 yrs has becker`s muscular dystrophy, should we use steroids? He is currently ambulatory but gets tired. We are giving him coq10, calcium and vit D supplement.

Using steroids is a very individual decision and one that you should discuss with your neuromuscular provider. While there are benefits to steroid use, there are also side effects. Much of the same molecular pathology is ongoing in Becker and Duchenne which are due to mutations in the same gene, and thus lessons from the much more common Duchenne are reasonable to apply to Becker, but the risk/benefit ratio may change depending on how severe the disease is, and other issues that your doctor can discuss.

Here are the recommendations from the CDC DMD Care Considerations:

--- Know when your son should start taking steroids.

Your doctor should start giving your son steroids when he reaches what doctors call a plateauphase. In DMD, the plateau phase is when your son

is not learning any new motor skills (crawling, walking, climbing stairs),

does not have trouble walking,

does not have trouble rising from the floor, and

does not have trouble climbing stairs.

After this plateau stage, it will be more difficult for your son to walk, rise from the floor, and climb stairs. Your son may stay in the plateau stage only a few months, so it important that you watch for this stage and tell your doctor about it. If your doctor does not offer steroids during your son’s plateau stage, your doctor should offer your son steroids when he starts to be less active.

--- Watch for side effects.

Steroids can cause serious side effects, including:

obesity

behavior problems

brittle bones

delayed puberty

stomach problems

cataracts

sensitivity to infections

Your doctor should be careful when starting your son on steroids if he already has any of the above issues, or if he has autism or attention deficit disorder, is overweight, or has overweight family members.

Question: Do we know how long these boys were on ACE or ARB's? Does that seem to matter?

We do not yet have that information gathered in DuchenneConnect, but presumably the medications would be having an effect over years of time.

Question: What age is considered early for ace inhibitor initiation?

Currently, starting ACE inhibitors at age 10 is considered “early.” As we continue to collect registry data, this age may change. Gathering information about the age at which the boys who are walking longer who take ACE inhibitors may support even earlier ages of initiation which some DMD Clinics are advocating.

No, unfortunately we do not have any data on doses of meds or supplements. We may begin to collect this data in the future. Your doctor or DMD Clinic may be able to give you guidance for various doses that are reasonable. While it is possible that people registered in DuchenneConnect may be using highly non-standard dosing, for Vitamin D, CoEnzyme Q10, Creatine, steroids, and ACE inhibitors there are published data of doses used in Duchenne and for other diseases to establish safe doses.

Question: If I want to switch from prednisone to ace inhibitor may I purchase the vitamins from Walgreens, CVS, etc or have the doctor prescribe them?

Both prednisone and ACE inhibitors are medications that require a prescription from your doctor. In addition, the results of this study indicate that the combination of ACE and steroids may be beneficial, so we would not recommend that your son stops taking prednisone. In fact, the observed benefit of ACE inhibitors was more strongly observed in the boys taking steroids.

Question:Are you finding that mutations early in the chain, particularly in the actin binding region, are more severe?

We are not observing that in the data, there are relatively fewer mutations in the beginning of the gene than towards the last third of the gene, so the numbers are not huge.

Question:Can we get insurance coverage for beneficial supplements...namely expensive ones like coQ10 and protandim?

We do not think so, but you should check with your insurance company, as every company has different policies regarding coverage. It may be that if a doctor prescribes them as a part of the medical treatment, that coverage is possible.

Question: Is there a recommended dosage of Creatine?

In the published studies using creatine, doses from 0.1gm/kg to 0.2g/kg have been used safely for months for a variety of purposes.